Earlier experiments by William C. Rose demonstrated that an oral source of histidine was not needed for the maintenance of nitrogen balance in young, adult human subjects and was a non-essential amino acid for adult men. Recently other authors have quustioned the conclusion that histidine was non-essential. The focus of this project is to ascertain the role of histidine in selected animals and to clarify the implied pathway of formation. In this connection, a recent rigorous, 72-day, experiment has been completed wherein an adult human was maintained for 48 days with all amino acids being delivered by intravenous alimentation. A 3-day lysine-free intake caused a marked, negative nitrogen balance. Deletion of histidine led to a continued apparent positive nitrogen balance for 27 days. Many components, including serum proteins, were constant throughout the 72 days. A decline in plasma and urinary histidine was observed during the histidine-devoid period. Many other tests of organ systems were performed. Further specific experiments to clarify these interrelationships and some ambiguities are being proposed. These and other findings must be considered in the evaluation of the essentiality of histidine for normal man.